5-HT2A receptor inverse agonist as well as preparation method and application thereof

Abstract

The invention relates to a novel compound as a 5-HT2A receptor inverse agonist, and a preparation method and a pharmaceutical composition thereof. The invention also relates to application of the compound or the pharmaceutical composition in preparation of drugs for treating 5-HT2A receptor related diseases, wherein the diseases comprise non-motor symptoms caused by Parkinson's disease, such as delusional disorder, hallusion, depression, anxiety, cognitive disorder and sleep disorder; dementia-related mental disorders; major depression; or negative symptoms of schizophrenia and the like.

Description

[0001] This application is a divisional application of PCT International Patent Application No. PCT / CN2023 / 111052, filed on August 3, 2023, entitled “5-HT 2A Receptor Antagonists, Methods of Making and Use Thereof,” which claims priority to U.S. Provisional Patent Application No. 63 / 271, 1 10, filed on October 8, 2021, the contents of which are incorporated by reference in their entirety into this application. TECHNICAL FIELD

[0002] The present application relates to a class of compounds as 5-hydroxytryptamine 2A (5-HT 2A ) receptor inverse agonists, methods of making the same, and uses thereof in the field of 5-HT 2A receptor related diseases. BACKGROUND

[0003] Parkinson’s disease (PD) is a common neurodegenerative disease with an average age of onset of 60 years old (Degirmenci, Yildiz. Cumhuriyet Medical Journal (2017), 39(3), 509-517.). According to the data of the National Institutes of Health (NIH) in 2018, there are about 4-6 million Parkinson’s disease patients worldwide, of which as many as 50% of Parkinson’s disease patients have hallucinations or delusions during the onset of the disease, which seriously affects the quality of life of patients and has a high incidence and mortality rate.

[0004] For a long time, antipsychotic drugs have been mainly used in the treatment of hallucinations and delusions in Parkinson’s disease patients. The first generation of antipsychotic drugs mainly inhibits dopamine D2 receptors, and has serious extrapyramidal side effects. The second generation of antipsychotic drugs, in addition to inhibiting D2 receptors, also more inhibits specific 5-HT receptors, especially 5-HT 2A receptors, has better safety, i.e., extrapyramidal side effects are smaller than the first generation of antipsychotic drugs. However, since the second generation of antipsychotic drugs still have D2 receptor inhibitory activity, they still have extrapyramidal side effects, and this class of drugs also has different degrees of side effects of weight gain. In 2016, the U.S. FDA approved Pimavanserin for marketing, which is used for the treatment of hallucinations and delusions in Parkinson’s disease patients, and became the first drug approved for this indication.

[0005]

[0006] Pimavanserin is a 5-HT 2AReceptor inverse agonists can eliminate the extrapyramidal and weight gain side effects associated with dopamine receptor inhibition of first and second generation antipsychotic drugs, and have better safety. 5-HT 2A is a major excitatory receptor subtype in the 5-HT receptor family, belonging to ligand-gated channels and G protein-coupled receptors. 5-HT 2A receptor function is closely related to neuronal excitation, behavioral effects, learning and memory, and anxiety, and is an important action target for antipsychotic drugs and schizophrenia treatment (Price, D. L., et al. Behavioural Pharmacology (2012), 23(4), 426-433.).

[0007] 5-HT 2A receptor has intrinsic activity and can produce effects in the absence of agonists. Pimavanserin as a 5-HT 2A receptor inverse agonist can inhibit the intrinsic activity of the receptor after binding to the 5-HT 2A receptor, so that the receptor does not function, and produces effects opposite to those of agonists, and can still show activity in the absence of agonists. While a typical 5-HT 2A receptor antagonist cannot cause biological effects after binding to the receptor, and can only show activity by inhibiting agonists (WO2004064738A2). Therefore, even if a compound has 5-HT 2A receptor antagonistic activity, it does not necessarily have 5-HT 2A receptor inverse agonistic activity.

[0008] 5-HT 2A receptor inverse agonists have good application prospects in the pharmaceutical industry as drugs, but only pimavanserin has been approved for marketing. Therefore, more 5-HT 2A receptor inverse agonists need to be developed to achieve better therapeutic effects and meet the needs of clinical patients. SUMMARY

[0009] In one aspect of the present application, the present application provides a compound represented by formula (I), a pharmaceutically acceptable salt, a stereoisomer or a deuterated form thereof: , wherein, R1 is selected from halogen; ring B is selected from , , , , , , , ; R2 is independently selected from hydrogen atoms, C atoms 1-3 Alkyl, C 3-6 cycloalkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C atom with the attached carbon atom. 3-6 cycloalkyl; Ring A is selected from , , , , , , ; X is selected from NR 6c , O or S; R 4a R 4b R 6a R 6b R 6c R 7a R 7b R 7c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

[0010] In some embodiments of the compound of formula (I): Ring A is selected from , , , , , , Preferred Other variables are as defined in this invention.

[0011] In some embodiments of the compound of formula (I): Ring B is selected from Preferred ; R3 is selected from halogens, or two R3 atoms attached to the same carbon atom form a carbon atom (C3) with the attached carbon atom. 3-6 Cycloalkyl; R3 is preferably F, or two R3s attached to the same carbon atom form a cyclopropyl group with the attached carbon atom; n is 1 or 2; other variables are as defined in this invention.

[0012] In some embodiments of the compound of formula (I): R5 is selected from -OR5', R5' is selected from C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 Alkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined in this invention.

[0013] In some embodiments of the compound of formula (I): R1 is selected from F; Ring B is selected from , , , , , , , Preferred ; R2 is selected from hydrogen atom, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl; Each R3 independently contains a hydrogen atom, F, and a methyl group, or two R3s attached to the same carbon atom can form a cyclopropyl group with the attached carbon atom. Ring A is selected from , , , , , , ; X is selected from NR 6c , O or S; R 4a R 4b R 6a R 6b R 6c R 7a R 7b R 7cEach is independently selected from hydrogen atoms, F, Cl, Br, methyl, and trifluoromethyl; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; n is selected from 0, 1, 2, and 3.

[0014] In some embodiments of the compound of formula (I): R1 is selected from F; Ring B is selected from , , Preferred ; R2 is selected from hydrogen atom, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl; R3 is selected from hydrogen atom, F, methyl, or two R3 attached to the same carbon atom to form a cyclopropyl group with the attached carbon atom; Ring A is selected from , , , , ; X is selected from NR 6c , O or S; R 4a R 4b R 6a R 6b R 6c R 7a R 7b R 7c Each is independently selected from hydrogen atoms, F, Cl, Br, methyl, and trifluoromethyl; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl. Preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl. n is selected from 0, 1, and 2.

[0015] In some embodiments of the compound of formula (I): R1 is selected from halogens; Ring B is selected from Preferred ; R2 is independently selected from hydrogen atoms, C atoms 1-3 alkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C atom with the attached carbon atom. 3-6 cycloalkyl; Ring A is selected from , , ; R 4a R 4b R 4c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl; n is selected from 1, 2, or 3; other variables are as defined in this invention.

[0016] In some embodiments of the compound of formula (I): R1 is selected from F; Ring B is selected from , , Preferred ; R2 is selected from hydrogen atom or methyl group; Ring A is selected from X is selected from NR 6c , O or S; R 6a R 6b R 6c Each is independently selected from hydrogen atom, F, Cl, Br, methyl, trifluoromethyl.

[0017] In some embodiments of the compound of formula (I): R1 is selected from F; Ring B is selected from , , Preferred ; R2 is selected from hydrogen atom or methyl group; R3 is selected from hydrogen atom, F, methyl, or two R3 attached to the same carbon atom to form a cyclopropyl group with the attached carbon atom; Ring A is selected from , , , , ; R 4a R 4b R 6a R 6b R 6c R 7a R 7b R 7c Each is independently selected from hydrogen atoms, F, Cl, Br, methyl, and trifluoromethyl; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; n is selected from 0, 1, and 2.

[0018] In some embodiments of the compound of formula (I): R1 is selected from halogens; Ring B is selected from ; R2 is independently selected from hydrogen atoms, C atoms 1-3 Alkyl, C 3-6 cycloalkyl; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 alkyl; Ring A is selected from , ; R 4a R 4b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6cycloalkyl, C 3-6 Halogenated cycloalkyl; preferably, R5' is selected from C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups.

[0019] In some embodiments of the compound of formula (I): R1 is selected from F; Ring B is selected from ; R2 is independently selected from hydrogen atom, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl; preferably methyl; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atom, F, methyl, or R. 3a With R 3b R 3c With R 3d R 3e With R 3f 、or R 3g With R 3h It forms a cyclopropyl group with the attached carbon atom; Ring A is selected from , ; R 4a and R 4b Each is independently selected from hydrogen atoms, F, Cl, and Br; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl.

[0020] In another aspect, the present invention provides compounds of formula (III), pharmaceutically acceptable salts thereof, stereoisomers or deuterated derivatives thereof:

[0021] in, R1 is selected from halogens; Ring B is selected from , , , , , , , ; R2 is independently selected from hydrogen atoms, C atoms 1-3 Alkyl, C 3-6 cycloalkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C atom with the attached carbon atom. 3-6 cycloalkyl; R 4a and R 4b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

[0022] In some embodiments of the compound of formula (III): Ring B is selected from Preferred ; R3 is selected from halogens, or two R3 atoms attached to the same carbon atom form a carbon atom (C3) with the attached carbon atom. 3-6 Cycloalkyl; R3 is preferably F, or two R3s attached to the same carbon atom form a cyclopropyl group with the attached carbon atom; n is 1 or 2; other variables are as defined in this invention.

[0023] In some embodiments of the compound of formula (III): R5' is selected from C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3Alkyl; preferably, R5' is selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; other variables are as defined in this invention.

[0024] In some embodiments of the compound of formula (III): R1 is selected from halogens; Ring B is selected from Preferred ; R2 is independently selected from hydrogen atoms, C atoms 1-3 alkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C atom with the attached carbon atom. 3-6 cycloalkyl; Ring A is selected from , , ; R 4a R 4b R 4c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl; n is selected from 1, 2, or 3; other variables are as defined in this invention.

[0025] In some embodiments of the compound shown in formula (III): R1 is selected from halogens; Ring B is selected from , , ; R2 is independently selected from hydrogen atoms, C atoms 1-3 alkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C atom with the attached carbon atom. 3-6 cycloalkyl; R 4a and R 4bEach is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl; n is selected from 0, 1, and 2.

[0026] In some embodiments of the compound shown in formula (III): R1 is selected from F; Ring B is selected from , , ; R2 is independently selected from hydrogen atoms and methyl groups; Each R3 is independently selected from hydrogen, F, Cl, Br, methyl, or two R3s attached to the same carbon atom can form a cyclopropyl group with the attached carbon atom. R 4a and R 4b Each is independently selected from hydrogen atoms, hydrogen atoms, F, Cl, and Br; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, 2,2-dimethylcyclopropylmethyl; n is selected from 0, 1, and 2.

[0027] In some embodiments of the compound shown in formula (III): R1 is selected from halogens; Ring B is selected from , , , , , , , ; R2 is independently selected from hydrogen atoms, C atoms 1-3 Alkyl, C 3-6 cycloalkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 alkyl; R 4aR 4b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups; n is selected from 0, 1, 2, and 3.

[0028] In some embodiments of the compound of formula (III): R1 is selected from F; Ring B is selected from , , , , , , , ; R2 is selected from hydrogen atom, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl; Each R3 has its own independent hydrogen atom, F, and methyl group; R 4a R 4b Each is independently selected from hydrogen atoms, F, Cl, Br, methyl, and trifluoromethyl; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, and 3,3-difluorocyclobutyl. n is selected from 0, 1, 2, and 3.

[0029] In some embodiments of the compound shown in formula (III): R1 is selected from halogens; Ring B is selected from ; R2 is independently selected from hydrogen atoms, C atoms 1-3 Alkyl, C 3-6 cycloalkyl; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, or R 3a With R 3b R 3c With R3d R 3e With R 3f 、or R 3g With R 3h It forms C with the attached carbon atom 3-6 cycloalkyl; R 4a and R 4b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups.

[0030] In some embodiments of the compound shown in formula (III): R1 is selected from F; Ring B is selected from ; R2 is independently selected from hydrogen atoms and methyl groups; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atom, F, methyl, or R. 3a With R 3b R 3c With R 3d R 3e With R 3f 、or R 3g With R 3h It forms a cyclopropyl group with the attached carbon atom; R 4a and R 4b Each is independently selected from hydrogen atoms, hydrogen atoms, F, Cl, and Br; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, and 2,2-dimethylcyclopropylmethyl.

[0031] In another aspect, the present invention provides compounds of formula (IIIA) or (IIIB), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives:

[0032] in, R1 is selected from halogens; R2 is selected from hydrogen atom, C 1-3 alkyl; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, or R 3a With R 3b R 3c With R 3d R 3e With R 3f 、or R 3g With R 3h It forms C with the attached carbon atom 3-6 cycloalkyl; R 4a and R 4b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl.

[0033] In some embodiments of the compounds shown in formula (IIIA) or (IIIB): R1 is selected from F; R2 is selected from hydrogen atom or methyl group; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atom, F, methyl, or R. 3a With R 3b R 3c With R 3d R 3e With R 3f 、or R3g With R 3h It forms a cyclopropyl group with the attached carbon atom; R 4a and R 4b Each is independently selected from hydrogen atoms, F, Cl, and Br; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, and 2,2-dimethylcyclopropylmethyl.

[0034] In another aspect, the present invention provides compounds of formula (IIIC), their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives:

[0035] in, R1 is selected from halogens; R2 is selected from hydrogen atom, C 1-3 alkyl; R 4a and R 4b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl.

[0036] In some embodiments of the compound shown in formula (II): R1 is selected from F; R2 is selected from hydrogen atom or methyl group; R 4a and R 4b Each is independently selected from hydrogen atoms, hydrogen atoms, F, Cl, and Br; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, and 2,2-dimethylcyclopropylmethyl.

[0037] In another aspect, the present invention provides compounds of formula (IV), pharmaceutically acceptable salts thereof, stereoisomers, or deuterated derivatives:

[0038] in, R1 is selected from halogens; R2 is selected from hydrogen atom, C 1-3 alkyl; R 6a R 6b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Halogenated alkyl groups; R 6c Selected from hydrogen atoms, C 1-3 alkyl.

[0039] In some embodiments of the compound shown in formula (IV): R1 is selected from F; R2 is selected from hydrogen atom or methyl group; R 6a R 6b Each is independently selected from hydrogen atoms, F, and trifluoromethyl groups; R 6c Selected from hydrogen atoms and methyl groups.

[0040] In another aspect, the present invention provides compounds of formula (V), pharmaceutically acceptable salts thereof, stereoisomers, or deuterated derivatives:

[0041] in, R1 is selected from halogens; R2 is selected from hydrogen atom, C 1-3 alkyl; R 7a R 7b R 7c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Halogenated alkyl groups.

[0042] In some embodiments of the compound shown in formula (V): R1 is selected from F; R2 is selected from hydrogen atom or methyl group; R 7a R 7b R 7c Each is independently selected from hydrogen atom, F, and trifluoromethyl.

[0043] In another aspect of the invention, the invention provides compounds of formula (VI), pharmaceutically acceptable salts thereof, stereoisomers or deuterated derivatives thereof:

[0044] in, R1a R 1b Each is independently selected from hydrogen atoms, C atoms 1-3 alkyl; Ring B is selected from , , , , , , , ; R2 is independently selected from hydrogen atoms, C atoms 1-3 alkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C atom with the attached carbon atom. 3-6 cycloalkyl; Ring A is selected from , , , , , , ; X is selected from NR 6c , O or S R 4a R 4b R 6a R 6b R 6c R 7a R 7b R 7c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

[0045] In some embodiments of the compound of formula (VI): R 1a R 1b Each is independently selected from hydrogen atoms, C atoms 1-3 alkyl; Ring B is selected from ; R2 is independently selected from hydrogen atoms, C atoms 1-3 Alkyl, C 3-6 cycloalkyl; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 alkyl; Ring A is selected from , ; R 4a R 4b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl groups.

[0046] In some embodiments of the compound of formula (VI): R 1a R 1b Each is independently selected from hydrogen atoms and methyl groups; Ring B is selected from ; R2 is independently selected from hydrogen atom, methyl, CD3, ethyl, n-propyl, isopropyl, cyclopropyl; R 3a R 3b R 3c R 3d R 3e R 3f R 3g R 3h Each is independently selected from hydrogen atom, F, methyl, or R. 3a With R 3b R 3c With R 3d R 3e With R 3f 、or R 3g With R 3h It forms a cyclopropyl group with the attached carbon atom; Ring A is selected from , ; R4a and R 4b Each is independently selected from hydrogen atoms, F, Cl, and Br; R5 is selected from -OR5', and R5' is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl, 3,3-difluorocyclobutyl, cyclopropylmethyl, and 2,2-dimethylcyclopropylmethyl.

[0047] In another aspect, the present invention provides compounds, pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives thereof, as shown below: , , , , , , , .

[0048] In another aspect, the present invention provides compounds, pharmaceutically acceptable salts or deuterated derivatives thereof, selected from: , , , , , .

[0049] In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of any of the above-described compounds or their stereoisomers or pharmaceutically acceptable salts, or a crystalline form of any of the above-described compounds and a pharmaceutically acceptable carrier. The carrier includes excipients conventional in the art, such as fillers, binders, diluents, disintegrants, lubricants, colorants, flavorings, antioxidants, or wetting agents.

[0050] The pharmaceutical composition can be formulated into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, suspensions, granules, powders, microparticles, pills, microtablets, fast-dissolving films, nasal sprays, transdermal patches, injections, or various sustained-release formulations. The pharmaceutical composition can be administered orally, via mucosal routes, rectally, or parenterally (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular, and intrasternal routes). The dosage can be appropriately adjusted according to the patient's age, sex, and disease type.

[0051] For oral administration, the pharmaceutical composition may be in the form of, for example, tablets, capsules, liquid capsules, suspensions, or liquids. The pharmaceutical composition is preferably prepared in dosage units containing a specific amount of the active ingredient. For example, the pharmaceutical composition may be provided as tablets or capsules containing an amount of the active ingredient ranging from about 0.1 to 1000 mg, preferably about 0.25 to 250 mg, and more preferably about 0.5 to 100 mg. The appropriate daily dose for human or other mammals can vary widely depending on the patient's condition and other factors, but can be determined using conventional methods.

[0052] In one aspect, the present invention provides any of the compounds described above, pharmaceutically acceptable salts thereof, or stereoisomers thereof for the treatment of 5-HT. 2A Application in medications for receptor-related diseases. These diseases or symptoms include: schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorders, dementia, anxiety disorders, sleep disorders, appetite disorders, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor tic disorders, depression, major depressive disorder, anxiety, sleep disturbances and appetite disorders, nonmotor symptoms of Parkinson's disease (including delusions, hallucinations, depression, anxiety, cognitive impairment, or sleep disturbances), dementia-related mental illnesses, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar atrophy, Tourette syndrome, Friedreich ataxia, Machado-Joseph disease, Lewy body dementia, motor disorders, dystonia, myoclonus, tremor, progressive supranuclear palsy, and frontotemporal dementia; or other disease states and conditions obvious to those skilled in the art.

[0053] Definitions and Explanations Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0054] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0055] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts, salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain specific compounds of this invention contain both basic and acidic functional groups, and thus can be converted into either a base or acid addition salt.

[0056] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, the salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0057] Some compounds of this invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of this invention.

[0058] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, ( R )- and( S - Enantiomers, diastereomers, ( D )-Isomer, ( L (Isomers, racemic mixtures thereof, and other mixtures, such as mixtures enriched with enantiomers or diastereomers, are all within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.)

[0059] Optically active materials can be prepared through chiral synthesis, chiral reagents, or other conventional techniques. R )-and( S )-Isomers and D and LIsomers. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, and then the diastereomeric isomer is resolved by conventional methods known in the art, and the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0060] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that can deliver an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient, including but not limited to: adhesives, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0061] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the quantity required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by a person skilled in the art through routine testing.

[0062] This invention is intended to include all isotopes of atoms present in the compounds of this invention. Isotopes include atoms with the same number of atoms but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include... 13 C and 14 C. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using a suitable isotope-labeling reagent instead of an additional unlabeled reagent.

[0063] The term "deuterated analog" refers to an analog produced by replacing one or more hydrogen atoms of a compound with deuterium atoms. The terms "optional" or "optionally" refer to events or conditions described subsequently that may occur but are not required, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur. For example, "optionally substituted with one or more deuterium atoms" means that the group may be unsubstituted or substituted with one or more deuterium atoms, i.e., it includes cases where the group is unsubstituted, partially substituted, and / or fully substituted.

[0064] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =O), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on aromatic groups.

[0065] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0066] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). For example, C1-C... 10 C represents 1 to 10 carbon atoms. 1-10 Selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 and C 10 Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), heptyl, octyl, nonyl, decyl, etc.

[0067] Unless otherwise specified, the term "halogen" or "halogen" itself or as part of another substituent indicates a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl straight-chain or branched haloalkoxy groups. For example, the term "C1-10 haloalkyl" is intended to include, but is not limited to, fluoromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3,3-difluoropropyl, 2,2'-difluoroisopropyl, 3,3,3-trifluoropropyl, 4-fluorobutyl, 4,4-difluorobutyl, 4,4,4-trifluorobutyl, 2-fluoro-2-methylpropyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.

[0068] Unless otherwise specified, cycloalkyl groups include any stable cyclic or polycyclic hydrocarbon group in which all carbon atoms are saturated, and which may be monosubstituted or polysubstituted, and may be monovalent, divalent, or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, etc. The cycloalkyl group may optionally be further substituted with halogens or C1-C3 alkyl groups.

[0069] Unless otherwise specified, "cycloalkylalkyl" refers to C 3-6 cycloalkyl-C 1-3 The alkyl group, or cycloalkyl group, may be substituted or unsubstituted, and non-limiting examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, etc. The cycloalkyl group may optionally be further substituted with a halogen or a C1-C3 alkyl group.

[0070] Compounds are named manually or using ChemDraw® software; commercially available compounds are named using supplier catalog names. Attached Figure Description

[0071] Figure 1 Number of head-shaking events in SD rats 1.0–1.5 h after a single oral administration (of which, # P <0.05, compared with the Control group;* P <0.05,** P <0.01, compared with the Model group). Detailed Implementation

[0072] The present invention will be further illustrated below with reference to specific embodiments and test examples, but this does not limit the scope of the invention in any way.

[0073] Example 1

[0074] Under nitrogen protection and in an ice-water bath, 2-(aminomethyl)-5-fluoropyridine (504 mg, 4.0 mmol) was dissolved in 10 mL of methanol, and N-methyl-4-piperidinone (452 ​​mg, 4.0 mmol) and sodium triacetoxyborohydride (933 mg, 4.4 mmol) were added. The mixture was then heated to room temperature and reacted for 15 h. The pH was adjusted to alkaline by adding sodium bicarbonate solution, the organic phase was concentrated, and then extracted with dichloromethane (10 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compounds 1-2 (538 mg).

[0075]

[0076] 16 mL of dimethyl sulfoxide, compound 1-3 (4.00 g, 1.00 g) eq ), compound trifluoroethanol (9.83 g, 3.00 g) eq Cesium carbonate (16.01 g, 1.50 eq) was added sequentially to a 100 mL three-necked flask, and the mixture was heated to 105 °C and maintained at this temperature for 12 hours. 200 mL of water was added to the reaction mixture, and the mixture was extracted twice with 200 mL of ethyl acetate each time. The organic phases were combined, washed with 200 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give compounds 1-4 (orange oil, 5.6 g).

[0077] Add 160 mL of tetrahydrofuran and compound 1-4 (4.0 g, 1.00 g) to the solution. eq Di-tert-butyl dicarbonate (4.32 g, 1.0 eq) and Raney nickel (1.7 g, 1.0 eq) were added sequentially to a 500 mL hydrogenation flask and reacted at 70 °C and 50 Psi for 12 hours. The mixture was filtered and evaporated to dryness to obtain a crude product. The crude product was purified by preparative chromatography to obtain compounds 1-5 (white solid, 2.37 g).

[0078] Ethyl acetate (5 mL), compounds 1-5 (1.00 g, 1.00 g) were added. eq ), HCl / EtOAc (5 mL) were added sequentially to a 100 mL single-necked flask, 25 o The mixture was kept at temperature and stirred for 17 hours. The reaction solution was directly evaporated to dryness to give crude compound 1-6 (pale pink solid, 903 mg).

[0079]

[0080] Add 2 mL of tetrahydrofuran and compound 1-6 (200 mg, 1.00 mL) to the solution. eq Diisopropylethylamine (DIEA) (125 mg, 1.00 eq) was added sequentially to a 10 mL single-necked flask, stirred for 15 minutes under a nitrogen atmosphere, and then cooled to 0°C in an ice-water bath. o C, carbonyl diimidazole (CDI) (173 mg, 1.10 eq Add to the reaction solution, 0 o Reacting at C for 1 hour, compounds 1-2 (216 mg, 1.0 mg) were added. eq Dissolve 1 mL of tetrahydrofuran and add it to the reaction solution. 25 o The mixture was kept at temperature and stirred for 12 hours. The reaction solution was concentrated to dryness to obtain a crude product. The crude product was purified by thin-layer chromatography and preparative chromatography to obtain compound 1 (yellow oil, 160 mg). 1 H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 2.5 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.41 -7.32 (m, 2H), 7.24 - 7.20 (m, 1H), 7.00 (br d, J = 2.1 Hz, 1H), 4.50 (d, J =5.4 Hz, 2H), 4.47 (s, 2H), 4.39 (q, J = 8.0 Hz, 2H), 4.27 (br s, 1H), 2.94(br d, J = 11.6 Hz, 2H), 2.32 (s, 3H), 2.20 - 2.08 (m, 2H), 1.82 (br dd, J =3.4, 12.1 Hz, 2H), 1.73 - 1.61 (m, 2H). MS m / z(ESI): 456.2[M+1].

[0081] Example 2 Compounds 2-4, 7-8, 11, 77, and 79 were obtained using a synthetic method similar to that in Example 1. The characterization data for compounds 2-4, 7-8, 11, 77, and 79 are listed in the table below: , , .

[0082] Example 3

[0083] 3 mL of tetrahydrofuran, compound 5-1 (300 mg, 1.00 eq), and diisopropylethylamine (282.10 mg, 1.50 eq) were added to a 100 mL single-necked flask. The mixture was cooled to 0 °C and stirred for 15 minutes under nitrogen protection. Carbonyl diimidazole (259.55 mg, 1.10 eq) was added to the reaction mixture, and the reaction was carried out at 0 °C for 1 hour. Then, dissolved compound 1-2 (324.92 mg, 1.00 eq) and 2 mL of tetrahydrofuran were added to the reaction mixture, and the reaction was carried out at 25 °C for 12 hours. The mixture was filtered and evaporated to dryness to obtain the crude product. The crude product was purified by preparative chromatography to obtain compound 5 (yellow solid, 440 mg). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.47 (d, J = 2.9 Hz, 1H), 8.04 (d, J = 1.9 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.29 (dd, J =4.4, 8.8 Hz, 1H), 7.15 (t, J = 5.6 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.96(q, J = 9.1 Hz, 2H), 4.46 (s, 2H), 4.21 (d, J = 5.5 Hz, 2H), 3.97 (br t, J =11.4 Hz, 1H), 2.88 (br d, J = 10.6 Hz, 2H), 2.26 (s, 3H), 2.16 (br t, J = 9.9Hz, 2H), 1.65 - 1.54 (m, 2H), 1.53 - 1.47 (m, 2H). MS m / z(ESI): 456.2 [M+1].

[0084] Example 4

[0085] 25 mL of methylpyrrolidone and compound 6-2 (2.55 g, 1.20 eq) were added to a 100 mL three-necked flask. The mixture was cooled to 0 °C, and sodium hydride (1.18 g, 1.50 eq) was added to the reaction solution in portions. The mixture was stirred at 0 °C for 0.5 hours. Compound 6-1 (2.40 g, 1.00 eq) was dissolved in 20 mL of methylpyrrolidone and added dropwise to the reaction solution. The mixture was stirred at 25 °C for 12 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted three times with 200 mL of ethyl acetate each time. The organic phase was dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 6-3 (white solid, 1.20 g).

[0086] 12 mL of tetrahydrofuran, compound 6-3 (1.20 g, 1.00 eq), di-tert-butyl dicarbonate (1.25 g, 1.00 eq), and Raney nickel (1.20 g, 2.45 eq) were added to a 250 mL hydrogenation flask and reacted at 70 °C and 50 Psi for 24 hours. The mixture was filtered, evaporated to dryness, and the crude product was purified by column chromatography to give compound 6-4 (white solid, 720 mg).

[0087] 2 mL of ethyl acetate and compound 6-4 (720 mg, 1.00 eq) were added to a 100 mL single-necked flask. Ethyl hydrochloride (8 mL, 4 M) was slowly added dropwise to the reaction mixture, and the reaction was carried out at 25 °C for 12 hours. The mixture was evaporated to dryness, dissolved in 10 mL of dichloromethane, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted three times with 10 mL of dichloromethane each time. The organic phase was dried, filtered, and evaporated to dryness to obtain compound 6-5 (440 mg).

[0088] 4 mL of tetrahydrofuran, compound 6-5 (390 mg, 1.00 eq), and diisopropylethylamine (352.96 mg, 1.50 eq) were added to a 100 mL single-necked flask. The mixture was cooled to 0 °C and stirred for 15 minutes under nitrogen protection. Carbonyl diimidazole (324.73 mg, 1.10 eq) was added to the reaction solution, and the reaction was incubated at 0 °C for 1 hour. Then, dissolved compound 1-2 (406.53 mg, 1.00 eq) and 2 mL of tetrahydrofuran were added to the reaction solution, and the reaction was incubated at 25 °C for 12 hours. The mixture was filtered and evaporated to dryness to obtain the crude product. The crude product was purified by preparative chromatography to obtain compound 6 (yellow gel-like substance, 460 mg). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.46(d, J = 2.9 Hz, 1H), 8.00 (d,J = 2.1 Hz, 1H), 7.69 - 7.59 (m, 2H), 7.30 (dd, J = 4.5, 8.8 Hz, 1H), 7.11 (t, J = 5.6 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H),5.13 - 5.02 (m, 1H), 4.46 (s, 2H), 4.19 (d, J = 5.5 Hz, 2H), 3.99 - 3.89 (m,1H), 3.20 - 3.07 (m, 2H), 2.81 (br d, J = 11.3 Hz, 2H), 2.74 - 2.61 (m, 2H),2.19 (s, 3H), 2.04 (br t, J = 10.9 Hz, 2H), 1.57 (dq, J = 3.4, 12.0 Hz, 2H),1.50 - 1.43 (m, 2H). MS m / z(ESI): 464.2 [M+1].

[0089] Example 5

[0090] Compound 19 was obtained using a synthesis method similar to that in Example 4. 1 H NMR (400 MHz, CDCl3) δ 8.30(d, J = 2.4 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.41 - 7.33 (m, 4H), 5.17 -5.14 (m, 1H), 4.38 (s, 2H), 4.35 - 4.34 (m, 2H), 4.32 - 4.28 (m, 1H), 3.14 -3.12 (m, 2H), 2.99 - 2.96 (m, 2H), 2.79 - 2.75 (m, 2H), 2.52 (br s, 1H), 2.35(s, 3H), 2.18 - 2.15 (m, 2H), 1.91 - 1.87 (m, 2H), 1.68 - 1.65 (m, 2H). MS(ESI) m / z : 482.2[M+1].

[0091] Example 6

[0092] Add 5 mL of N,N-dimethylformamide and compound 9-1 (300 mg, 1.00 mL) to a container. eq Diisopropylethylamine (265 mg, 1.00 eq) was added sequentially to a 10 mL single-necked flask. The mixture was stirred for 15 minutes under a nitrogen atmosphere and then cooled to 0 °C in an ice-water bath. Carbonyl diimidazole was then added. (366 mg, 1.10 eq Add the compound 1-2 (504 mg, 1.0 g) to the reaction solution and react at 0 °C for 1 hour. eq The compound was dissolved in 2 mL of DMF and added to the reaction solution. The mixture was stirred at 25 °C for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted three times with 50 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give compound 9 (yellow oil, 310 mg). 1 HNMR (400 MHz, CDCl3) δ 8.38 (br s, 1H), 8.23 ​​(d, J = 2.6 Hz, 1H), 7.52 (s, 1H), 7.35 - 7.29 (m, 3H), 7.21 (t, J = 2.8Hz, 1H), 7.11 (dd, J = 1.5, 8.4 Hz, 1H), 6.66 (br s, 1H), 6.50 (ddd, J = 0.8,2.0, 3.0 Hz, 1H), 4.51 (d, J = 5.1 Hz, 2H), 4.39 (s, 2H), 4.34 (br t, J = 4.1Hz, 1H), 2.95 (br d, J = 11.5 Hz, 2H), 2.32 (s, 3H), 2.14 (br t, J = 11.1 Hz, 2H), 1.89 - 1.76 (m, 2H), 1.73 - 1.66 (m, 2H). MS m / z(ESI): 396.2[M+1].

[0093] Example 7

[0094] Add 5 mL of N,N-dimethylformamide and compound 10-1 (300 mg, 1.00 mL) to a container. eq Diisopropylethylamine (245 mg, 1.00 eq) was added sequentially to a 10 mL single-necked flask. After stirring for 15 minutes under a nitrogen atmosphere, the mixture was cooled to 0°C in an ice-water bath. Then, carbonyl diimidazole (338 mg, 1.10 eq) was added... eq The compound 1-2 was added to the reaction solution and reacted at 0 °C for 1 hour. Compounds 1-2 were dissolved in 2 mL of DMFN,N-dimethylformamide and added to the reaction solution. The mixture was kept at 25 °C and stirred for 12 hours. 40 mL of water was added to the reaction solution, and the mixture was extracted twice with 50 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 10 (yellow oil, 200 mg). 1 H NMR (400 MHz, CDCl3) δ 8.89 (dd, J =1.6, 4.3 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.13 - 8.03 (m, 2H), 7.72 - 7.63(m, 2H), 7.45 - 7.35 (m, 3H), 4.62 (d, J = 5.5 Hz, 2H), 4.44 (s, 2H), 4.39 -4.26 (m, 1H), 2.99 (br d, J = 11.5 Hz, 2H), 2.36 (s, 3H), 2.19 (br t, J =11.1 Hz, 2H), 1.98 - 1.82 (m, 2H), 1.71 (br dd, J = 1.9, 11.8 Hz, 2H). MS m / z(ESI): 408.2[M+1].

[0095] Example 8

[0096] 5 mL of tetrahydrofuran, compound 5-1 (400 mg, 1.00 eq), and diisopropylethylamine (376 mg, 1.50 eq) were added to a 100 mL single-necked flask. The mixture was cooled to 0 °C and stirred for 15 minutes under nitrogen protection. Carbonyl diimidazole (346 mg, 1.10 eq) was added to the reaction solution, and the reaction was carried out at 0 °C for 1 hour. Then, dissolved compound 39-1 (635 mg, 1.00 eq) and 4 mL of tetrahydrofuran were added to the reaction solution, and the reaction was carried out at 25 °C for 12 hours. The mixture was filtered to obtain the filtrate. The filtrate was purified by preparative chromatography to obtain compound 39-2 (yellow oil, 400 mg, yield: 33.5%).

[0097] 20 mL of dichloromethane, compound 39-2 (350 mg, 1.00 eq), and trifluoroacetic acid (6 mL, 129 eq) were added to a 100 mL single-necked flask, stirred at 25 °C for 20 minutes, and evaporated to dryness to obtain a yellow oily substance. 20 mL of tetrahydrofuran, a yellow oil, sodium cyanoborohydride (78 mg, 2.00 eq), and 37% formaldehyde aqueous solution (76 mg, 1.50 eq) were added to a 100 mL single-necked flask. The mixture was stirred at 25 °C for 20 minutes, evaporated to dryness, and 10 mL of methanol was added. The mixture was stirred at 75 °C for 80 minutes, evaporated to dryness, and the crude product was obtained. The crude product was chirally separated (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​EtOH)]; B%: 20%-20%) to give compound 39 (retention time: 1.778 min, yellow viscous, 120 mg, yield: 39.9%) and compound 41 (retention time: 1.876 min, yellow viscous, 130 mg, yield: 43.3%).

[0098] Compound 39: 1 H NMR (400 MHz, DMSO- d 6 ) δ8.47 (d, J = 2.9 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.34 (dd, J = 4.5, 8.8 Hz, 1H), 7.20 (t, J = 5.6 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.96 (q, J = 9.1 Hz, 2H), 4.71 - 4.45 (m, 3H), 4.29 - 4.14 (m, 2H), 4.13 - 3.99 (m, 1H), 3.13 - 3.04(m, 1H), 2.66 (br d, J = 10.6 Hz, 1H), 2.18 (s, 3H), 1.99 - 1.87 (m, 2H), 1.62 - 1.52 (m, 2H). MS m / z(ESI): 474.3[M+1].

[0099] Compound 41: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.47 (d, J = 2.9 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.70 - 7.62 (m, 2H), 7.35 (dd, J = 4.5, 8.8 Hz, 1H), 7.20 (t, J = 5.6 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.97 (q, J = 9.1 Hz, 2H), 4.62 - 4.45 (m, 3H), 4.28 - 4.14 (m, 2H), 4.12 - 4.01 (m, 1H), 3.13 - 3.06(m, 1H), 2.66 (br d, J = 11.0 Hz, 1H), 2.18 (s, 3H), 1.98 - 1.87 (m, 2H), 1.64 - 1.51 (m, 2H). MS m / z(ESI): 474.3[M+1].

[0100] Example 9

[0101] Compound 39-2 (360 mg, 1) eqAdd to 3.3 ml of ethyl acetate, then add HCl / EtOAc (4M, 2.41 mL, 15) eq The reaction was carried out at room temperature for 12 hours. The reaction solution was concentrated and evaporated to dryness to obtain the crude product. The pH was adjusted to 7 by adding sodium bicarbonate aqueous solution, and the solution was concentrated and evaporated to dryness again. The crude product was chirally separated (column: DAICEL CHIRALPAKAD (250mm*30mm, 10μm); mobile phase: [A:CO2, B:(0.1%NH3H2O ​​EtOH)]; B%: 20%-20%), concentrated and lyophilized to obtain compound 56A (retention time: 1.744 min, yellow oil, 95.0 mg, yield: 30.0%) and compound 56B (retention time: 2.519 min, yellow oil, 90 mg, yield: 29.4%).

[0102] Compound 56A: 1 H NMR (400 MHz, CDCl3) δ 1.76 - 1.83 (m, 2 H), 2.58 - 2.68 (m, 2 H), 3.03 (br d, J =12.26 Hz, 1 H), 3.36 - 3.48 (m, 1 H), 4.27 (td, J =10.66, 5.19 Hz, 1 H), 4.35 (br d, J =5.38 Hz, 2 H), 4.45 - 4.50 (m, 2 H), 4.59- 4.67 (m, 1 H), 4.71 - 4.78 (m, 2 H), 6.54 - 6.69 (m, 1 H), 6.81 (d, J =8.50Hz, 1 H), 7.35 - 7.43 (m, 2 H), 7.57 (dd, J =8.44, 2.31 Hz, 1 H), 7.97 - 8.06(m, 1 H), 8.30 (d, J =2.38 Hz, 1 H). MS(ESI) m / z: 460.2[M+1].

[0103] Compound 56B: 1 H NMR (400 MHz, CDCl3) δ1.67 (br s, 2 H), 2.52 (br d, J=3.50 Hz, 2 H), 2.86 - 2.98 (m, 1 H), 3.30 (br s, 1 H), 4.14 (br s, 1 H), 4.23(br s, 2 H), 4.37 (br s, 2 H), 4.53 (br s, 1 H), 4.63 (br d, J=6.13 Hz, 2 H), 6.41 - 6.61 (m, 1 H), 6.69 (br d, J=5.88 Hz, 1 H), 7.27 (br s, 2 H), 7.37 -7.52 (m, 1 H), 7.91 (br s, 1 H), 8.18 (br s, 1 H). MS(ESI) m / z: 460.2[M+1].

[0104] Example 10 Compounds 27-28, 42, 44, 66 / 67, 69A / 69B, and 70A / 70B were obtained using synthetic and / or resolution methods similar to those in Example 8. Compounds 46A / 46B, 47A / 47B, 72A / 72B, 81A / 81B, and 82A / 82B were obtained using the following resolution conditions (column: DAICEL CHIRALCEL OX (250mm*50mm, 10μm); mobile phase: [A:CO2, B:(0.1%NH3H2O ​​EtOH)]; B%: 25%-25%). The characterization data of the relevant compounds are listed in the table below. , , , , , , , , , .

[0105] Example 11

[0106] 20 mL of tetrahydrofuran and compound 57-1 (1.80 g, 1.00 eq) were added to a 100 mL three-necked flask, and the mixture was cooled to 0 °C. Lithium aluminum hydride (954 mg, 2.00 eq) was added in portions to the reaction mixture, and the mixture was stirred at 25 °C for 12 hours. Then, 1 mL of water, 1 mL of 15% sodium hydroxide aqueous solution, and 3 mL of water were added sequentially to the reaction mixture. The mixture was extracted three times with ethyl acetate, the organic phase was dried, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative chromatography to obtain compound 57-2 (620 mg, yield: 32.8%).

[0107] 6 mL of tetrahydrofuran, compound 57-2 (570 mg, 1.00 eq), and diisopropylethylamine (750 mg, 1.50 eq) were added to a 100 mL single-necked flask. The mixture was cooled to 0 °C and stirred for 15 minutes under nitrogen protection. Carbonyl diimidazole (690 mg, 1.10 eq) was added to the reaction solution, and the reaction was continued at 0 °C for 1 hour. Compound 1-2 (864 mg, 1.00 eq) was then added to the reaction solution, and the reaction was continued at 25 °C for 12 hours. The mixture was filtered to obtain the crude product. The crude product was purified by preparative chromatography to obtain compound 57 (off-white solid, 950 mg, yield: 60.9%). 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.47 (d, J = 2.8 Hz, 1H), 7.95 (d, J = 2.1 Hz, 1H), 7.65 (dt, J = 2.9, 8.8 Hz, 1H), 7.52 - 7.45(m, 2H), 7.34 (dd, J = 4.5, 8.6 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.92 (d, J =1.4 Hz, 1H), 4.49 (s, 2H), 4.36 (br d, J = 5.5 Hz, 2H), 3.96 (br t, J = 11.5Hz, 1H), 2.71 (br d, J = 11.1 Hz, 2H), 2.09 (s, 3H), 1.94 - 1.83 (m, 2H), 1.61 - 1.50 (m, 2H), 1.49 - 1.41 (m, 2H). MS (ESI) m / z: 397.2 [M+1].

[0108] Example 12 Compounds 12-13, 58-61, and 84 were obtained using a synthetic method similar to that used in Example 11. The characterization data for compounds 12-13, 58-61, and 84 are listed in the table below: , .

[0109] Example 13

[0110]

[0111] 30 mL of acetonitrile, compound 17-1 (10.0 g, 1.00 eq), and triethylamine (4.15 g, 1.00 eq) were sequentially added to a 100 mL three-necked flask under N2 protection. Trifluoroacetic anhydride (9.47 g, 1.10 eq) was added in portions, and the reaction temperature was controlled at 35 ℃–40 ℃. The reaction was maintained at 40 ℃ for half an hour. The mixture was diluted with 30 mL of water, filtered, and the filter cake was collected and dried under vacuum to obtain compound 17-2 (yellow oil, 11.8 g, yield: 85.3%).

[0112] Cesium carbonate (23.96 g, 2.50 eq), cuprous iodide (840 mg, 0.15 eq), and L-proline (2.27 g, 1.0 eq) were added sequentially to a 100 mL three-necked flask. 20 mL of N,N-dimethylformamide was added to the reaction flask, and the reaction was carried out at 25 °C for 15 minutes. Compound 17-2 (10 g, 1.00 eq) was dissolved in 10 mL of N,N-dimethylformamide and slowly added dropwise to the reaction solution. The reaction was carried out at 25 °C for 15 minutes. Tert-butyl acetoacetate (9.3 g, 2.00 eq) was added to the reaction solution, and the reaction was maintained at 90 °C for 12 hours. After the reaction was complete, the contents of the container were cooled to 18-23 °C. Water (40 mL) was added for more than 15 seconds, and the reaction temperature was maintained below 35 °C. Then add isopropyl acetate (40 mL), toluene (80 mL), and water (40 mL). Drain the aqueous layer and wash with a saturated ammonium chloride solution (50 mL). Then reduce the organic layer to a minimum by vacuum distillation. Add dichloromethane (30 mL) and adjust the internal temperature to 18 °C–23 °C. Add trifluoroacetic acid (10 mL) and continue for 15 minutes. Stir the solution overnight. Filter the solid and wash twice with dichloromethane, 20 mL each time. Give compound 17-3 (yellow solid, 3.52 g, yield: 47.7%).

[0113] 5 mL of 1-methyl-2-pyrrolidone, 0.5 mL of water, and compound 17-3 (1.0 g, 1.00 eq) were sequentially added to a 50 mL single-necked flask. The reaction was maintained at 130 °C for 12 hours. After cooling to room temperature, 30 mL of water was added, and the mixture was stirred for 40 min. The mixture was then filtered. The filter cake was washed with water, and the product was dried under vacuum. The crude product was purified by column chromatography to give compound 17-4 (white solid, 760 mg, yield: 46.1%).

[0114] 15 mL of N,N-dimethylformamide, compound 17-4 (750 mg, 1.00 eq), and sodium hydride (356.85 mg, 60% purity, 2.50 eq) were added sequentially to a 50 mL three-necked flask, and the reaction was carried out at room temperature for 30 minutes. Iodomethane (1.01 g, 2.00 eq) was added to the reaction mixture in portions at 0 °C, and the reaction was carried out at room temperature for 2 hours. 150 mL of ice water was added to the reaction mixture, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined, dried, and concentrated to dryness to give compound 17-5 (white solid, 790 mg, yield: 92%).

[0115] 50 mL of tetrahydrofuran, compound 17-5 (790 mg, 1.00 eq), di-tert-butyl dicarbonate (769 mg, 1.00 eq), and Raney nickel (1.00 g, 3.31 eq) were added sequentially to a 200 mL hydrogenation flask and reacted at 70 °C, 50 Psi, and H2 for 16 hours. The mixture was filtered and evaporated to dryness to obtain compound 17-6 (white solid, 1.62 g, crude product).

[0116] 5 mL of ethyl acetate, compound 17-6 (1.62 g, 1.00 eq), and HCl / EtOAc (4 M, 20.0 mL, 16.21 eq) were added sequentially to a 50 mL single-necked flask. The reaction was carried out at room temperature for 2 hours. The mixture was then evaporated to dryness. The crude product was purified by preparative chromatography to give compound 17-7 (yellow oil, 297 mg, yield: 25.4%).

[0117] 4 mL of tetrahydrofuran, compound 1-2 (78.33 mg, 1.00 eq), and diisopropylethylamine (141.5 mg, 1.10 eq) were added sequentially to a 50 mL three-necked flask, and the reaction was carried out at room temperature for 15 min. Carbonyl diimidazole (195.39 mg, 1.10 eq) was added to the reaction solution at 0 °C, and the reaction was carried out at 0 °C for one hour. After detecting the reaction intermediate, compound 17-7 (244 mg, 1.00 eq) was added to the reaction solution, and the reaction was carried out at room temperature for 12 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted twice with 20 mL of dichloromethane each time. The organic phases were combined, washed with 20 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by preparative chromatography to obtain compound 17 (white solid, 145 mg, yield: 27.2%). 1 H NMR (400MHz, CDCl3) δ 8.22 (d, J = 2.5 Hz, 1H), 7.59 (s, 1H), 7.44 - 7.37 (m, 3H), 7.33 (s, 2H), 6.89 (s, 1H), 4.52 (d, J = 5.3 Hz, 2H), 4.49 - 4.43 (m, 1H),4.41 (s, 2H), 3.84 (s, 3H), 3.28 (br d, J = 11.6 Hz, 2H), 2.58 (s, 3H), 2.56- 2.48 (m, 2H), 2.17 (dq, J = 3.2, 12.6 Hz, 2H), 1.75 (br d, J = 11.6 Hz, 2H). MS (ESI) m / z : 478.2 [M+1].

[0118] Example 14

[0119] Compound 30-1 (10.0 g, 1.00 eq) was slowly added dropwise to 100 mL of sulfuric acid (184 g, 35.8 eq, 75% purity) at 0°C, and stirred for 10 minutes. Sodium nitrite dissolved in 81 mL of water was then slowly added dropwise at 0°C, with the temperature maintained between 5 and 10 °C throughout. o C. Stir the mixture in an ice-water bath for 3 hours. Add 50 mL of ammonia to the reaction solution in an ice-water bath, filter the reaction solution, wash the filter cake with 100 mL of water and concentrate it to dryness to obtain compound 30-2 (yellow solid, 9.0 g, yield: 89.6%).

[0120] 40 mL of dimethyl sulfoxide, compound 30-2 (4.0 g, 1.00 eq), trifluoroiodoethane (4.93 g, 1.50 eq), and cesium carbonate were added. (10.2 g, 2.00 eq) were added sequentially to a 250 mL three-necked flask, 100 o Stir at C for 1 hour. Add 350 mL of water to the reaction mixture, extract three times with 100 mL of ethyl acetate each time, combine the organic phases, and extract twice with 100 mL of saturated brine each time. Dry the organic phase and concentrate it to dryness to obtain the crude product. The crude product is purified by column chromatography to give compound 25-3 (yellow solid, 1.3 g, yield: 24.6%).

[0121] 12 mL of N-methylpyrrolidone, compound 30-3 (1.20 g, 1.00 eq), and zinc cyanide were added. (229 mg, 0.55 eq) were added sequentially to a 100 mL three-necked flask, and tetraphenylphosphine palladium was added under a nitrogen atmosphere. 130 o The mixture was kept at room temperature and stirred for 12 hours. 100 mL of water was added to the reaction mixture, and the mixture was extracted three times with 100 mL of ethyl acetate each time. The organic phases were combined and extracted twice with saturated brine, 50 mL each time. The organic phase was dried and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give compound 30-4 (white solid, 400 mg, yield: 47.5%).

[0122] 5 mL of tetrahydrofuran, compound 30-4 (300 mg, 1.00 eq), di-tert-butyl dicarbonate (276 mg, 1.00 eq), and Raney nickel (300 mg, 2.76 eq) were sequentially added to a 100 mL tempered glass bottle under an argon atmosphere. Under hydrogen catalysis, 50 Psi and 70 Psi were added... o The mixture was stirred at room temperature (C) for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 30-5 (yellow oil, 60 mg, yield: 27.7%).

[0123] Add 0.5 mL of ethyl acetate, compound 30-5 (100 mg, 1.00 eq), and HCl / EtOAc (1 mL) sequentially to a 10 mL single-necked flask. Incubate at 25°C. o The mixture was kept at a constant temperature and stirred for 6 hours. The reaction solution was concentrated to dryness to obtain crude compound 30-6 (yellow solid, 20 mg), which was used directly in the next reaction.

[0124] 1 mL of tetrahydrofuran, compound 30-6 (20 mg, 1.00 eq), and diisopropylethylamine (10.7 mg, 1.00 eq) were added sequentially to a 10 mL single-necked flask. The mixture was stirred for 15 minutes under a nitrogen atmosphere and then cooled to 0°C in an ice-water bath. o C, add carbonyl diimidazole (14.8 mg, 1.10 eq) to the reaction solution, 0 o After reacting at C for 1 hour, compounds 1-2 (20 mg, 1.00 eq) dissolved in 0.5 mL of tetrahydrofuran were added to the reaction solution. 25 o The mixture was stirred at room temperature (C) for 12 hours. 10 mL of water was added to the reaction mixture, and the solution was extracted twice with ethyl acetate, 5 mL each time. The organic phases were combined and extracted twice with saturated brine, 5 mL each time. The organic phases were dried and concentrated to dryness to obtain the crude product. The crude product was purified to obtain compound 30 (white solid, 10 mg, yield: 24.3%). 1 H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.72 (br s, 1H), 7.47 (s,1H), 7.44 - 7.41 (m, 2H), 6.72 (s, 1H), 4.57 (q, J = 8.6 Hz, 2H), 4.39 (s,2H), 4.27 (br s, 1H), 4.23 (d, J = 5.9 Hz, 2H), 3.10 (br d, J = 11.6 Hz, 2H), 2.44 (s, 3H), 2.32 (br t, J = 11.4 Hz, 2H), 2.14 - 2.13 (m, 1H), 2.07 (br d,J = 11.4 Hz, 1H), 1.67 (br d, J = 11.9 Hz, 2H). MS (ESI) m / z: 490.2 [M+1].

[0125] Example 15

[0126] Dichloromethane (30 mL), compound 29-1 (2.80 g, 1.00 mL) were added. eq ) and p-fluorobenzaldehyde (4.92 g, 1.00 g) eq Add the following to a 100 mL three-necked flask at room temperature and stir well. Then add sodium triacetoxyborohydride (9.56 g, 2.00 g) eqThe organic phase was added to the reaction solution and stirred at room temperature for 16 hours. Then, 30 mL of saturated sodium bicarbonate solution was added to the reaction solution and stirring was continued for 10 minutes. The mixture was allowed to stand and separate into layers, separating the organic phase. The aqueous phase was extracted three times with 15 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was first purified by column chromatography, and then purified by preparative separation to obtain compound 29-2 (colorless oil, 1.20 g).

[0127] Tetrahydrofuran (15 mL), compound 5-1 (1.04 g, 1.00 mL) were added. eq, HCI Add the following ingredients sequentially to a 100 mL three-necked flask, and under nitrogen atmosphere, add diisopropylethylamine (1.11 g, 2.00 g) dropwise. eq The mixture was stirred at 20°C for 15 minutes. Then, it was cooled to 0°C, and carbonyl diimidazole (765 mg, 1.10 mg) was added in portions to the reaction solution. eq The reaction was tested and it was found that compound 5-1 had reacted completely. Compound 29-2 (1.40 g, 1.00 g) was added. eq The compound was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction solution. The mixture was kept at 25 °C and stirred for 12 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted three times with 50 mL of ethyl acetate each time. The organic phases were combined, washed with 80 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give compound 29-3 (colorless oil, 966 mg, yield: 38.8%).

[0128] Anhydrous dichloromethane (27 mL), compound 29-3 (966 mg, 1.00 mL) were added. eq ), trifluoroacetic acid (15.4 g, 78.0 g) eq The mixture was added sequentially to a 50 mL single-necked flask and stirred at 25 °C for 20 minutes. The reaction solution was evaporated to dryness to give crude compound 29-4 (pale yellow oil, 850 mg, yield: 91.4%).

[0129] Tetrahydrofuran (8 mL), compound 29-4 (800 mg, 1.00 mL) were added. eq Sodium cyanoborohydride (219 mg, 2.00 mg) eq Formaldehyde (212 mg, 37%, 1.50 mg) eqThe solutions were added sequentially to a 50 mL single-necked flask. The mixture was kept at 25°C and stirred for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted three times with 30 mL of ethyl acetate each time. The organic phases were combined, washed with 40 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was first purified by column chromatography, and then separated by SFC (column: DAICL CHIRALCEL OX (250mm*50mm, 10μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​EtOH)]; B%: 25%-25%) to obtain compound 68A (retention time: 1.457 min, white solid, 159 mg, yield: 23.1%), compound 68B (retention time: 1.707 min, white solid, 163 mg, yield: 24.4%), compound 68C (retention time: 1.935 min, white solid, 142 mg, yield: 21.2%) and compound 68D (retention time: 2.356 min, white solid, 133 mg, yield: 19.8%).

[0130] Compound 68A: 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 2.3, 8.5 Hz, 1H), 7.17 - 7.08 (m, 2H), 7.00 (br t, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 5.17 - 4.99 (m, 1H), 4.94 (br t, J = 5.1 Hz, 1H), 4.71 (d, J = 8.6 Hz, 2H), 4.56 - 4.43 (m, 2H), 4.30 - 4.17 (m, 2H), 3.81 -3.57 (m, 2H), 3.22 - 2.91 (m, 2H), 2.80 (s, 3H), 2.60 - 2.45 (m, 1H), 1.79(br d, J = 11.8 Hz, 1H). MS(ESI) m / z: 473.2[M+1].

[0131] Compound 68B: 1 H NMR (400 MHz, CDCl3) δ7.88 (d, J J = 2.0 Hz, 1H), 7.37(dd, J J = 2.3, 8.4 Hz, 1H), 7.15 (dd, J J = 5.3, 8.4 Hz, 2H), 7.06 - 6.98 (m,2H), 6.76 (d, J J = 8.5 Hz, 1H), 5.16 - 4.97 (m, 1H), 4.85 (br t, J J = 5.1 Hz,1H), 4.76 - 4.70 (m, 2H), 4.52 (br d, J J = 13.3 Hz, 2H), 4.32 - 4.19 (m, 2H),3.64 (br t, J J = 11.8 Hz, 1H), 3.52 (br d, J J = 10.8 Hz, 1H), 3.08 - 2.80 (m,2H), 2.74 (s, 3H), 2.59 - 2.44 (m, 1H), 1.78 (br d, J J = 11.5 Hz, 1H). MS(ESI) m / z : 473.2[M+1].

[0132] Compound 68C: 1 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J J = 1.9 Hz, 1H), 7.44(dd, J J = 2.3, 8.5 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.02 (br t, J J = 8.5 Hz, 2H),6.77 (d, J J = 8.5 Hz, 1H), 4.76 - 4.70 (m, 3H), 4.58 - 4.38 (m, 3H), 4.30 -4.27 (m, 2H), 3.24 - 3.21 (m, 1H), 2.85 - 2.82 (m, 1H), 2.34 (s, 3H), 2.21 -2.12 (m, 2H), 1.82-1.80 (m, 2H). MS(ESI) m / z : 473.2[M+1].

[0133] Compound 68D:1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 2.0 Hz, 1H), 7.43(dd, J = 2.3, 8.4 Hz, 1H), 7.27 - 7.20 (m, 2H), 7.06 - 6.98 (m, 2H), 6.77 (d, J = 8.5 Hz, 1H), 4.76 - 4.70 (m, 3H), 4.58 - 4.38 (m, 3H), 4.30 - 4.27 (m,2H), 3.24 - 3.21 (m, 1H), 2.85 - 2.82 (m, 1H), 2.34 (s, 3H), 2.21 - 2.12 (m,2H), 1.82-1.80 (m, 2H). MS(ESI) m / z: 473.2[M+1].

[0134] Example 16

[0135] Add 30 mL of methanol and compound 50-1 (2.00 g, 1.00 g) to a container. eq Ammonium acetate (1.37 g, 2.00 g) eq Add the following ingredients sequentially to a 250 mL three-necked flask, stir at 20 ℃ for 1 hour, sodium cyanoborohydride (1.12 g, 2.00 g) eq After adding the compound to the reaction mixture, the mixture was stirred at 60 °C for 12 hours until the reaction was complete. The reaction solution was concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 50-2 (yellow liquid, 1.80 g, yield: 89.9%).

[0136] Add 20 mL of dichloromethane and compound 50-2 (1.80 g, 1.00 g) to the solution. eq ), p-fluoropyridine formaldehyde (999 mg, 1.00 mg) eq The ingredients were added sequentially to a 100 mL three-necked flask, and the mixture was stirred at 30 °C for 6 hours under nitrogen protection. Then, sodium triacetate borohydride (3.37 g, 2.00 g) was added. eq The mixture was stirred at 30 °C for 13 hours, then cooled to room temperature. Water (10 mL) was added to quench the reaction, and the mixture was extracted twice with 10 mL of dichloromethane each time. The organic phases were combined and washed twice with 10 mL of saturated brine. The organic phases were dried and concentrated to dryness to obtain the crude product. The crude product was separated by high-performance liquid chromatography to obtain compound 50-3 (yellow liquid, 1.30 g).

[0137] Add 15 mL of tetrahydrofuran and 1-trifluoroethoxy-4-pyridinemethylamine (800 mg, 1.00 mL) to a solution of 1-trifluoroethoxy-4-pyridinemethylamine. eq N,N-diisopropylethylamine (1.00 g, 2.00 g) eq The mixture was added sequentially to a 100 mL round-bottom flask and reacted at 20 °C under nitrogen for 15 minutes. The reaction temperature was then lowered to 0 °C, and carbonyl diimidazole (754 mg, 1.20 g) was added. eq After stirring for another 0.5 hours, add 10 mL of tetrahydrofuran and compound 50-3 (1.30 g, 1.00 g). eq The solution of [component name] was added, and the reaction was heated to 80 °C and stirred for 24 hours until the reaction was complete. 20 mL of water was added to the reaction solution, and the mixture was extracted twice with 30 mL of ethyl acetate each time. The organic phases were combined, washed with 60 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by high-performance liquid chromatography to obtain compound 50-4 (yellow liquid, 900 mg, yield: 40.9%).

[0138] Add 8 mL of dichloromethane and compound 50-4 (900 mg, 1.00 mg) to the solution. eq ), trifluoroacetic acid (6.14g, 33.9g) eq The contents were added sequentially to a 100 mL three-necked flask, and the mixture was reacted at 10 °C for 1 hour under nitrogen protection. The reaction mixture was concentrated to dryness to obtain compound 50-5 (yellow liquid, 910 mg, crude trifluoroacetate), which was used directly in the next step.

[0139] Add 20 mL of dichloromethane and compound 50-5 (950 mg, 1.00 mL) to the solution. eq, triflate Formaldehyde solution (200 mg, 1.51 mg) eq ) , sodium cyanoborohydride (205 mg, 2.00 eqThe solutions were added sequentially to a 100 mL three-necked flask and stirred at 25 °C for 13 hours. The reaction was cooled to 0 °C, quenched with 20 mL of sodium bicarbonate aqueous solution, and extracted twice with 30 mL of dichloromethane each time. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was prepared by high performance liquid chromatography and chiral chromatography (column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​IPA)]; B%: 25%-25%) to give compounds 50A (retention time: 1.259 min, yellow liquid, 90.0 mg, yield: 11.2%) and 50B (retention time: 1.460 min, yellow liquid, 120 mg, yield: 14.8%).

[0140] Compound 50A: 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.8 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.60 (dd, J 1 = 2.4 Hz J 2 =8.4 Hz, 1H), 7.38 - 7.37 (m, 1H),7.25 - 7.23 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.53 (br, 1H), 4.79 - 4.72 (m,2H), 4.44 - 4.26 (m, 5H), 2.99 -2.92 (m, 1H), 2.55 -2.54 (m, 1H) 2.27 (s,3H), 2.20 -2.17 (m, 1H), 2.07 - 2.03 (m, 2H), 1.73 -1.70 (m, 1H), 0.57 -0.45 (m, 3H), 0.26 -0.24 (m, 1H). MS(ESI) m / z: 482.2[M+1].

[0141] Compound 50B: 1 H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 2.8 Hz, 1H), 8.03 (d, J= 2.0 Hz, 1H), 7.60 (dd, J 1 = 2.4 Hz J 2 =8.4 Hz, 1H), 7.38 - 7.37 (m, 1H),7.26 - 7.23 (m, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.54 (br, 1H), 4.79 - 4.72 (m,2H), 4.48 - 4.19 (m, 5H), 3.00 -2.92 (m, 1H), 2.58 -2.54 (m, 1H) 2.28 (s,3H), 2.20 -2.18 (m, 1H), 2.11 - 2.04 (m, 2H), 1.73 -1.70 (m, 1H), 0.52 -0.47 (m, 3H), 0.27 -0.25 (m, 1H). MS(ESI) m / z: 482.2[M+1].

[0142] Example 17 Compounds 49A / 49B and 83A / 83B were obtained using a synthesis and resolution method similar to that used in Example 16. The characterization data for compounds 49A / 49B and 83A / 83B are listed in the table below: ,

[0143] Example 18

[0144] Dichloromethane (110 mL), compound 85-1 (22.0 g, 1.00 mL) were added. eq Compound p-fluorophenylethylamine (14.0 g, 1.10 g) eq The contents were added sequentially to a 250 mL three-necked flask and stirred at 20°C for 6 hours. After the reaction was complete, sodium triacetoxyborohydride (32.3 g, 1.50 g) was added. eq The mixture was stirred at 20°C for 12 hours. After the reaction was complete, 80 mL of water was added to the reaction solution, and the mixture was extracted twice with 80 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain crude product 85-2 (yellow oily substance, 33.5 g, crude product).

[0145] Dichloromethane (670 mL), compound 85-2 (33.5 g, 1.00 mL) were added.eq Triethylamine (28.6 mL, 2.00 mL) eq ), trifluoroacetic anhydride (17.1 mL, 1.20) eq ), 4-Dimethylaminopyridine (6.27 g, 0.50 g) eq The organic phases were added sequentially to a 1 L three-necked flask and stirred at 20 °C for 1 hour. After the reaction was complete, the mixture was washed twice with 400 mL of water each time. The organic phases were combined, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain compound 85-3 (yellow oil, 37.5 g, yield: 69.2%).

[0146] Dichloromethane (187 mL), compound 85-3 (37.5 g, 1.00 mL) were added. eq ), trifluoroacetic acid (33.0 mL, 5.00 mL) eq The mixture was added sequentially to a 500 mL three-necked flask and stirred at 20°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to dryness to obtain crude compound 85-4 (yellow oil, 28.6 g, yield: 100%).

[0147] Tetrahydrofuran (286 mL), compound 85-4 (28.6 g, 1.00 mL) were added. eq Formaldehyde aqueous solution (33.1 mL, 37% purity, 5.00) eq Add the sodium cyanoborohydride (11.2 g, 2.00 g) sequentially to a 500 mL three-necked flask, adding it in batches. eq The mixture was stirred at 20°C for 1.5 hours. After the reaction was complete, the pH was adjusted to 8 with a saturated sodium carbonate aqueous solution, and the mixture was extracted twice with 100 mL of dichloromethane each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give crude product 85-5 (yellow oil, 34.5 g, yield: 87.7%).

[0148] Add water (217 mL), compound 85-5 (32.5 g, 1.00 mL) to the solution. eq ), concentrated hydrochloric acid (325 mL, 12.0 M, 40.4 g / L). eq The contents were added sequentially to a 1 L three-necked flask and stirred at 100 °C for 12 hours. After the reaction was complete, the pH was adjusted to 8-9 with 156 g of sodium hydroxide, and the mixture was extracted twice with dichloromethane, 400 mL each time. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain the crude product. The crude product was chirally separated to obtain compound 85-6 (yellow oil, 2.19 g, crude product).

[0149] (1-Methyl-1H-indol-5-yl)methylamine (333 mg, 1.00 mg) eq Add to 5 ml of tetrahydrofuran, then add diisopropylethylamine (672 mg, 906 μL, 2.50 mg / L). eq The reaction solution was cooled to 0°C, and carbonyl diimidazole (371 mg, 1.10 g) was added. eq After stirring for another hour, add compound 85-6 (500 mg, 1.00 mg) dissolved in 3 ml of tetrahydrofuran. eq The reaction solution was heated to 70°C and reacted for 12 hours. After the reaction was complete, water was added and the mixture was extracted with dichloromethane. The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by preparative separation to obtain compound 85 (white solid, 760 mg, yield: 85.6%). Further separation by SFC (column: DAICEL CHIRALCEL OX (250 mm * 50 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​EtOH)]; B%: 25%-25%) yielded compound 85A (retention time: 2.018 min, white solid, 266 mg, yield: 41.7%) and compound 85B (retention time: 2.461 min, white solid, 235 mg, yield: 36.3%).

[0150] Compound 85A: 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.22 - 7.15 (m, 3H), 7.04 (d, J = 3.0 Hz, 1H), 6.98 (t, J = 8.6 Hz, 2H), 6.95 - 6.91 (m, 1H), 6.39(d, J = 2.9 Hz, 1H), 5.04 - 4.86 (m, 1H), 4.68 - 4.61 (m, 2H), 4.57 (s, 1H), 4.49 (s, 1H), 4.45 - 4.41 (m, 2H), 3.77 (s, 3H), 3.19 (br t, J = 11.9 Hz,1H), 3.03 - 2.95 (m, 1H), 2.40 (br d, J= 13.3 Hz, 1H), 2.34 (s, 3H), 2.24 -2.16 (m, 2H), 1.66-1.61 (m, 1H). MS(ESI) m / z: 427.2 [M+1].

[0151] Compound 85B: 1 H NMR (400 MHz, CDCl3) δ 7.24 (s, 1H), 7.21 - 7.15 (m, 3H), 7.05 - 7.03 (m, 1H), 7.01 - 6.96 (m, 2H), 6.94 - 6.91 (m, 1H), 6.39 (d, J =2.9 Hz, 1H), 5.04 - 4.86 (m, 1H), 4.68 - 4.61 (m, 2H), 4.59 - 4.56 (m, 1H), 4.52 - 4.48 (m, 1H), 4.45 - 4.41 (m, 2H), 3.77 (s, MS(ESI) m / z : 427.2 [M+1].

[0152] Example 19 Compounds 86A and 86B, and compounds 87A / 87B, were obtained using a synthesis and resolution method similar to that used in Example 18. The characterization data for compounds 86A and 86B, and 87A and 87B, are listed in the table below: ,

[0153] Example 20

[0154] Hydrochloric acid (6 M, 120 mL, 17.2 ppm) was added to a 500 mL round-bottom flask at 0 °C. eq Compound 88-1 (8 g, 41.88 mmol, 1) was added to the mixture. eq Then add sodium nitrite (2.89 g, 41.88 mmol, 1...). eqA 10 mL solution of petroleum ether was added to the solution, and the mixture was stirred at 38 °C for 8 hours. The reaction mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give compound 88-2 (3.5 g, 18.23 mmol, yield 43.5%) as a white solid.

[0155] Compound 88-2 (2.8 g, 14.58 mmol, 1 eq ) and cesium carbonate (9.50 g, 29.17 mmol, 2 eq Add 10.16 g, 43.75 mmol, 3% trifluoromethanesulfonate to a 28 mL xyleneamine mixture. eq The mixture was stirred at 50 °C for 1 hour. The reaction mixture was filtered and washed with ethyl acetate (100 mL * 3). The organic layer was washed with saturated sodium chloride aqueous solution (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give compound 88-3 (3 g, 10.95 mmol, yield 75.1%) as a colorless oil.

[0156] Compound 88-3 (700 mg, 2.55 mmol, 1) eq ), N-aminomethyltrifluoroborate potassium (726.75 mg, 3.07 mmol, 1.2 eq ), potassium phosphate (1.63 g, 7.66 mmol, 3 eq ), Mesylate [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (93.02 mg, 0.128 mmol, 0.05 mg) eq The compound was dissolved in dioxane (10 mL) and water (2 mL), purged three times with nitrogen, and then stirred at 80 °C under nitrogen for 1 hour. The mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with saturated brine (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give compound 88-4 (0.7 g, 2.16 mmol, yield 84.5%) as a pale yellow solid.

[0157] Compound 88-4 (300 mg, 0.925 mmol, 1) eq2-chloropyridine (315.14 mg, 2.78 mmol, 3) was added to a 10 mL solution of dichloromethane. eq ) and trifluoroacetic anhydride (391.53 mg, 1.39 mmol, 1.5 mmol) eq The mixture was then stirred at 20 °C for 1 hour, followed by the addition of 3-fluoro-N-[(4-fluorophenyl)methyl]-1-methyl-piperidin-4-amine (489.07 mg, 2.04 mmol, 2.2 mg) at 20 °C. eq The resulting mixture was stirred at 20 °C for another hour. The mixture was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with saturated brine (20 mL * 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (dichloromethane / methanol = 1 / 0 ~ 10 / 1) and then separated by SFC (column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 μm); mobile phase: [A: CO2, B: (0.1% NH3H2O ​​MeOH)]; B%: 15%-15%) to give compound 88A (retention time: 1.025 min, 123 mg, yield 26.3%) as a white solid and compound 88B (retention time: 1.231 min, 116 mg, yield 25.1%) as a white solid.

[0158] Compound 88A: 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.76 - 7.64 (m, 1H), 7.25 - 7.15 (m, 2H), 7.15 - 7.05 (m, 2H), 6.99 (t, J = 5.6 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.92 (q, J = 9.2 Hz, 2H), 4.82 - 4.59 (m, 2H), 4.41 (d, J = 17.6 Hz,1H), 4.29 - 4.08 (m, 3H), 2.97 (t, J= 12.0 Hz, 1H), 2.83 - 2.70 (m, 1H), 2.24 - 2.04 (m, 4H), 2.02 - 1.86 (m, 2H), 1.41 - 1.22 (m, 1H). MS(ESI) m / z: 491.3 [M+1].

[0159] Compound 88B: 1 H NMR (400 MHz, DMSO- d 6 ) δ 7.70 (t, J = 8.8 Hz, 1H), 7.25 -7.15 (m, 2H), 7.14 - 7.04 (m, 2H), 7.03 - 6.93 (m, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.92 (q, J = 8.8 Hz, 2H), 4.82 - 4.58 (m, 2H), 4.41 (d, J = 18.0 Hz,1H), 4.30 - 4.05 (m, 3H), 2.97 (t, J = 11.6 Hz, 1H), 2.82 - 2.70 (m, 1H), 2.24 - 2.04 (m, 4H), 2.02 - 1.85 (m, 2H), 1.41 - 1.20 (m, 1H). MS(ESI) m / z: 491.3 [M+1].

[0160] Example 21

[0161] Compound 89A (retention time: 0.994 min, white solid) and compound 89B (retention time: 1.055 min, white solid) were obtained using a synthesis and resolution method similar to that in Example 20.

[0162] Compound 89A: 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 3.3 Hz, 1H), 7.56 (s,1H), 7.14 - 7.07 (m, 3H), 6.96 (br t, J= 8.5 Hz, 2H), 4.92 - 4.74 (m, 1H), 4.66 - 4.56 (m, 2H), 4.54 - 4.34 (m, 3H), 4.13 (br s, 3H), 4.08 - 4.02 (m,1H), 3.08 (br dd, J = 7.9, 12.8 Hz, 1H), 2.76 - 2.66 (m, 2H), 2.29 - 2.23 (m,4H), 2.20 - 2.09 (m, 2H), 1.41 - 1.22 (m, 1H). MS(ESI) m / z: 499.2 [M+1].

[0163] Compound 89B: 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 3.3 Hz, 1H), 7.67 -7.61 (m, 1H), 7.23 - 7.11 (m, 2H), 7.09 - 6.95 (m, 3H), 5.01 - 4.81 (m, 1H), 4.70 (s, 1H), 4.66 - 4.42 (m, 3H), 4.33 - 4.21 (m, 3H), 3.39 (t, J = 7.1 Hz,1H), 3.26 - 3.05 (m, 3H), 3.02 (br dd, J = 1.9, 3.9 Hz, 1H), 2.89 - 2.71 (m,2H), 2.20 - 2.09 (m, 4H), 1.41 - 1.22 (m, 1H). MS(ESI) m / z: 499.2 [M+1].

[0164] Example 22

[0165] Tetrahydrofuran (15 mL), compound 5-1 (1.04 g, 1.00 mL) were added. eq, HCI Add the following ingredients sequentially to a 100 mL three-necked flask, and under nitrogen atmosphere, add diisopropylethylamine (1.11 g, 2.00 g) dropwise. eq The mixture was stirred at 20°C for 15 minutes. Then, it was cooled to 0°C, and N,N'-carbonyldiimidazole (765 mg, 1.10 mg) was added to the reaction solution in portions. eqThe reaction was tested and it was found that compound 5-1 had completely reacted. Compound 68-1 (1.40 g, 1.00 g) was added. eq The compound was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction solution. The mixture was kept at 25 °C and stirred for 12 hours. 100 mL of water was added to the reaction solution, and the mixture was extracted three times with 50 mL of ethyl acetate each time. The organic phases were combined, washed with 80 mL of saturated brine, dried, and concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography to give compound 68-2 (colorless oil, 966 mg, yield: 38.8%).

[0166] Anhydrous dichloromethane (27 mL), compound 68-2 (966 mg, 1.00 mL) were added. eq ), trifluoroacetic acid (15.4 g, 78.0 g) eq The mixture was added sequentially to a 50 mL single-necked flask and stirred at 25 °C for 20 minutes. The reaction solution was evaporated to dryness to give crude compound 68-3 (pale yellow oil, 850 mg, yield: 91.4%).

[0167] Tetrahydrofuran (8 mL), compound 68-3 (800 mg, 1.00 mL) were added. eq Sodium cyanoborohydride (219 mg, 2.00 mg) eq Formaldehyde (212 mg, 37%, 1.50 mg) eq The solutions were added sequentially to a 50 mL single-necked flask. The mixture was incubated at 25°C with stirring for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted three times with 30 mL of ethyl acetate each time. The organic phases were combined, washed with 40 mL of saturated brine, dried, concentrated to dryness, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to give compound 68A (white solid, 643 mg, yield: 78.1%). 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 2.3, 8.5 Hz, 1H), 7.17 - 7.08 (m,2H), 7.00 (br t, J = 8.5 Hz, 2H), 6.75 (d, J = 8.5 Hz, 1H), 5.17 - 4.99 (m,1H), 4.94 (br t, J = 5.1 Hz, 1H), 4.71 (d, J= 8.6 Hz, 2H), 4.56 - 4.43 (m,2H), 4.30 - 4.17 (m, 2H), 3.81 - 3.57 (m, 2H), 3.22 - 2.91 (m, 2H), 2.80 (s,3H), 2.60 - 2.45 (m, 1H), 1.79 (br d, J = 11.8 Hz, 1H). MS(ESI) m / z: 473.2[M+1].

[0168] Experimental Example 1. 5-HT 2A Receptor reverse agonist activity test 1.1 Experimental Materials: Cell line: Adherent cells NIH3T3-5-HT 2A R Cell culture medium: DMEM + 10% FBS (purchased from GBICO) Cell culture plates: 96-well plates with white walls and transparent bottoms (purchased from Perkin Elmer) Test kit: Bright-Glo™ Luciferase (purchased from Promega) Testing instrument: BioTek multi-functional microplate reader 1.2 Test Drugs Pimovanseline: Purchased from MCE Other compounds: prepared according to the foregoing examples 1.3 Experimental Methods: The logarithmic growth phase of NIH 3T3-5HT 2A R cells were seeded at a density of 1000 cells per well in 96-well plates with a clear white background and incubated overnight at 37°C in a 5% CO2 incubator. The next day, the test compound was added to the cells at a maximum concentration of 10 μM. Nine concentrations were serially diluted 3.16-fold with PBS, with each concentration in duplicate. PBS served as the negative control, and pimozide at the same concentration served as the positive control. After drug addition, the cells were incubated at 37°C in a 5% CO2 incubator for 120 h. On the sixth day, an equal volume of Bright-Glo™ Luciferase reagent was added to the cells, and the plates were incubated at room temperature in the dark for 20 min. The plates were shaken every 5 min, and the luminescence intensity was measured using a microplate reader. The cell inhibition rate was calculated, and the data were processed using GraphPadPrism 7.0 to obtain the cell inhibition rate curve and calculate the IC50. 50 The experimental results are shown in Table 1.

[0169] Cell inhibition rate (%) = [100 - (Lum test drug - Lum culture medium) / (Lum cell control - Lum culture medium) × 100] .

[0170] Experimental Example 2. hERG Inhibitory Activity

[0171] 1. Experimental materials and instruments 1.1 Positive control compound Name: Cisapride 1.2 Solvent Name: DMSO (Dimethyl sulfoxide) 1.3 Cells Species & Strain: CHO-hERG cell line (Chinese hamster ovary cells stably expressing the hERG channel) Culture medium: 90% F12, 10% fetal bovine serum, 100 μg / mL G418, 100 μg / mL Hygromycin B Culture conditions: 5% CO2, 37℃ incubator Freezing conditions: liquid nitrogen 1.4 Experimental Apparatus Patch clamp amplifiers (Axoclamp 200B, Multiclamp 700B, Axon, USA) Digital-to-analog converters (DigiData 1440A, DigiData 1550B, Axon, USA) Inverted microscopes (IX51, IX71, Olympus, Japan) Rapid drug delivery system (RSC-200, Bio-Logic, France) Micromanipulator (MX7600R, Syskiyou, USA) Electrode drawing apparatus (P-97, Sutter, USA) Glass electrode (BF150-86-10, Sutter, USA) Vibration damping platform and shielding mesh (63-534, TMC, USA) Data acquisition and analysis software (pClamp 10, Axon, USA) CO2 incubator (HERAcell 150i, Thermo, USA) Biosafety cabinet (MODEL 1384, Thermo, USA) Pure water system (Milli Q, Millipore, USA) 2. Experimental Methods 2.1 Cell Culture and Treatment CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes at 37°C in a 5% CO2 incubator, and passaged every 48 hours at a 1:5 ratio. On the day of the experiment, the cell culture medium was aspirated, the cells were rinsed once with extracellular fluid, and then 0.25% Trypsin-EDTA (Invitrogen) solution was added for digestion at room temperature for 3-5 minutes. The digestion solution was aspirated, the cells were resuspended in extracellular fluid, and transferred to experimental dishes for electrophysiological recording.

[0172] 2.2 Compound Preparation On the day of testing, the compound was diluted to an intermediate concentration with DMSO. 10 μL of the intermediate concentration compound was transferred to 4990 μL of extracellular fluid and diluted 500-fold to obtain the final concentration required for testing.

[0173] Preparation of positive control compound Cisapride: Take 10 μL of 150 μM Cisapride DMSO stock solution and transfer it to 4990 μL of extracellular fluid. Dilute 500 times to obtain the final concentration of 300 nM to be tested.

[0174] 2.3 Electrophysiological Recording Process CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were simply inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV to induce hERG potassium current (Ik). hERG The step voltage was applied from -80 mV to +20 mV for 2 seconds, then repolarized to -50 mV for 1 second before returning to -80 mV. This voltage stimulation was applied every 10 seconds, and the drug administration process began after the hERG potassium current stabilized (1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells were tested for each concentration (n≥2).

[0175] 2.4 Data Processing and Analysis Data analysis was performed using pClamp 10 and GraphPad Prism 5.0 software.

[0176] The formula for calculating the degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations is as follows: Inhibition % = [1 – (I / Io)]×100% Where Inhibition % represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0177] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 5 software, and the experimental results are shown in Table 1: Y=Bottom + (Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0178] 3. Experimental Results Table 1. In vitro test results of the compounds of the present invention

[0179] The results showed that the 5-HT of several compounds of the present invention 2A Its reverse agonistic activity is superior to pimovaserine, and its cardiotoxicity is lower.

[0180] Experimental Example 3. Evaluation of In Vitro Liver Microsomal Stability 1. Solution preparation 1) Preparation of working solution for test sample: Dilute the test sample with methanol to 100 µM; 2) Preparation of working solution for liver microsomes: Dilute liver microsomes with 100 mM phosphate buffer to 0.56 mg / ml; 3) Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) working solution: Weigh an appropriate amount of NADPH and dilute it to 20 mM with phosphate buffer, then add an equal volume of 60 mM MgCl2 solution. 4) Preparation of stop solution: Dilute toluenebutyrate to 20 ng / mL with acetonitrile to prepare the stop solution containing internal standard.

[0181] 2. Incubation process 1) Prepare incubation anti-adsorption EP tubes, and label the species, test sample, control (testosterone, dextromethorphan), time points (0, 5, 10, 20, 30, 60 min, Blank60, NCF60), etc. 2) Add 2 µL of the test sample or control working solution and 178 µL of liver microsome working solution to each tube. Add 2 µL of acetonitrile to the Blank tube instead of the test sample. Incubate in a 37°C water bath for about 10 min. Each sample is repeated in triplicate. 3) After the pre-incubation, except for 0 min and NCF60, add 20 µL of NADPH working solution to each tube to start the reaction. Add 20 µL of phosphate buffer (containing 30 mM MgCl2) to the NCF60 tube. The final concentration of the test sample or control in the incubation system is 1 µM, the final concentration of liver microsomes is 0.5 mg / mL, the final concentration of NADPH is 1 mM, and the final concentration of MgCl2 is 3 mM. 4) For the 0 min sample, first add 600 µL of stop solution and then add NADPH working solution. After each sample has been incubated for the corresponding time, add 600 µL of stop solution to terminate the reaction. 5) After the reaction of each sample is terminated, vortex for 30s, then centrifuge at 13500 rpm for 10 min. Take 100 µL of supernatant into an EP tube, add 100 µL of Milli-Q water, vortex and mix well, and then perform LC-MS / MS analysis.

[0182] 6) Testosterone and dextromethorphan were used as positive controls under the same conditions to test the stability and reliability of the system.

[0183] 3. Data Analysis The percentage of the test sample remaining after 60 minutes of testing is shown in Table 2.

[0184] Table 2. Experimental data of the compounds of the present invention in human, canine and rat liver microsomes.

[0185] The results showed that several compounds of the present invention exhibited better stability in in vitro canine and human liver microsomes than pimovaserine, and thus possessed better drug-like properties.

[0186] Example 4. In vivo pharmacodynamic evaluation 1. Experimental Design Based on in vivo pharmacokinetic data of a series of compounds, the drug reached C60 levels 1.0–1.5 h after a single oral gavage administration in SD rats. max At this time point, SD rats were intraperitoneally injected with 4-iodine-2,5-dimethoxy-A-methyl-phenylethylamine hydrochloride (DOI, 5-HT). 2A(Receptor agonist), administered at a dose of 2.5 mg / kg, to induce head-shaking behavior in SD rats, thus establishing the model.

[0187] The low, medium, and high dose groups of compound 68A were set at 0.22, 0.66, and 2.0 mg / kg, respectively. Pimovanserine tartrate (Pim-T) was set at 0.7 mg / kg. Both compounds 68A and Pim-T were administered orally via gavage.

[0188] 2. Experimental grouping and drug administration The compound was dissolved in DMSO:20% solvent (5%:95%). SD rats (200g-250g) were randomly divided into 6 groups according to body weight: solvent control group, model group, Pim-T 0.7 mg / kg group, and compound 68A 0.22, 0.66, and 2.0 mg / kg groups, with 7 animals in each group. Animal grouping and administration information are detailed in Table 3. Table 3: Animal grouping and administration .

[0189] Note: The dosages of Pim-T (pimovan serin tartrate) and compound 68A are calculated as free base.

[0190] 3. Experimental Procedure Rats were fasted at 5 PM the day before the experiment. On the day of the experiment, the animals were allowed to acclimatize in the testing laboratory for at least 1 hour. Each group of rats was administered the drug via a single gavage at the dosages shown in Table 3. One hour after administration, all groups except the Control group received an intraperitoneal injection of 2.5 mg / kg DOI. The Control group received an equal volume of physiological saline. Rats' behavior was observed immediately after injection. The observations were randomized and double-blind to exclude human interference. The number of head-shaking events in the rats within 1.0–1.5 hours after drug administration was recorded.

[0191] Experimental data are expressed as mean ± standard error (Mean ± SEM). One-way ANOVA was used in SPSS Statistics 20.0 software to compare differences between groups at each time point. All tests were two-tailed. P <0.05 indicates statistical significance.

[0192] 4. Data Analysis Compared with the control group, the number of head-shaking events in the model group rats was significantly increased. P <0.05). Compared with the model group, the number of head-shaking events in rats in the Pim-T 0.7 mg / kg group was significantly reduced ( P<0.05%, the number of head-shaking events in rats in the compound 68A 0.22, 0.66, and 2.0 mg / kg groups was significantly reduced ( P <0.01). At equimolar doses, the number of head-shaking events in rats in the compound 68A 0.66 mg / kg group was lower than that in the Pim-T 0.7 mg / kg group. Specific results are shown in Table 4 and Appendix. Figure 1 .

[0193] Table 4: Number of head-shaking events in SD rats 1.0–1.5 h after a single oral administration

[0194] Note: # P <0.05, compared with the Control group;* P <0.05,** P <0.01, compared with the Model group.

[0195] The results showed that 1.0–1.5 h after a single oral administration to SD rats, compound 68A significantly inhibited head-shaking frequency in rats within a dose range of 0.22–2.0 mg / kg, with an effective dose of 0.22 mg / kg. At equimolar doses, compound 68A was more effective than Pim-T.

[0196] Example 5. Evaluation of in vivo tissue distribution

[0197] 1. Experimental Design Compound 68A was administered to SD rats (200g-250g) via a single gavage at a dose of 11 mg / kg. Plasma and brain, heart, liver, and lung tissues were collected at 0.25h, 1h, and 6h after administration, with 3 animals at each time point.

[0198] 2. Experimental Procedure Rats were fasted around 6 PM the day before the experiment, but given free access to water. On the day of the experiment, rats were weighed and randomly divided into three groups based on body weight, with one group of animals at each time point. The compound was dissolved in DMSO:20% solvent (5%:95%). Rats were administered compound 68A via gavage at a dose of 11 mg / kg, with a volume of 5 mL / kg, resulting in a concentration of 2.2 mg / mL. At each collection time point, animals were anesthetized with ether, and approximately 1 mL of blood was collected from the heart. This blood was placed in a heparinized EP tube, centrifuged at 10,000 rpm for 10 min, and plasma was separated. After perfusion of the heart to remove blood, brain, heart, liver, and lung tissues were collected. Blood was blotted dry with filter paper, and each tissue was weighed. The weighing paper was then wrapped and stored at -80℃ for later analysis.

[0199] 3. Sample Measurement and Data Analysis Plasma samples and tissue homogenates (water homogenization of each tissue at a weight-to-volume ratio of 1:4) were pretreated and then analyzed by LC-MS / MS to determine the concentration of analytes in plasma and each tissue. Experimental data are expressed as mean ± standard deviation (Mean ± SD). Specific results are shown in Table 5.

[0200] Table 5: Plasma and tissue concentrations of compound 68A after a single gavage administration in SD rats

[0201] The results showed that the concentration of compound 68A in tissues was higher than that in plasma at 0.25h, 1h and 6h after a single oral administration to SD rats, indicating that compound 68A has good permeability; in particular, its distribution in brain tissue was high, with a brain-to-blood ratio of 9.51 to 10.5, and the concentration in the brain remained stable between 0.25h and 6h.

Claims

1. The compound represented by formula (I), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: ， in, R1 is selected from halogens; Ring B is selected from , , , , , , , ; R2 is independently selected from hydrogen atoms, C atoms 1-3 Alkyl, C 3-6 cycloalkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C3 group with the attached carbon atom. 3-6 cycloalkyl; Ring A is selected from , , , , , , ; X is selected from NR 6c Or S; R 4a R 4b R 6a R 6b R 6c R 7a R 7b R 7c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

2. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein it is the compound of formula (III), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: ， in, R1 is selected from halogens; Ring B is selected from , , , , , , , ; R2 is independently selected from hydrogen atoms, C atoms 1-3 Alkyl, C 3-6 cycloalkyl; Each R3 is independently selected from hydrogen, halogen, and C atoms. 1-3 Alkyl groups, or two R3 atoms attached to the same carbon atom, form a C3 group with the attached carbon atom. 3-6 cycloalkyl; R 4a and R 4b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Alkyl, C 1-3 Halogenated alkyl groups; R5 is selected from -OR5', R5' is selected from C 1-6 Haloalkyl, C 3-6 cycloalkyl, C 3-6 Halogenated cycloalkyl, C 3-6 cycloalkyl C 1-3 Alkyl, optionally C 1-3 Alkyl-substituted C 3-6 cycloalkyl C 1-3 alkyl; n is selected from 0, 1, 2, and 3.

3. The compound according to any one of claims 1-2, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein, Ring B is selected from Preferred ; R3 is selected from halogens, or two R3 atoms attached to the same carbon atom form a carbon atom (C3) with the attached carbon atom. 3-6 Cycloalkyl; R3 is preferably F, or two R3s attached to the same carbon atom form a cyclopropyl group with the attached carbon atom; n is 1 or 2.

4. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein the compound is a compound of formula (IV), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: ， in, R1 is selected from halogens; R2 is selected from hydrogen atom, C 1-3 alkyl; R 6a R 6b Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Halogenated alkyl groups; R 6c Selected from hydrogen atoms, C 1-3 alkyl.

5. The compound according to claim 1, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein the compound is a compound of formula (V), its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative: ， in, R1 is selected from halogens; R2 is selected from hydrogen atom, C 1-3 alkyl; R 7a R 7b R 7c Each is independently selected from hydrogen atoms, halogens, and C atoms. 1-3 Halogenated alkyl groups.

6. The compound of claim 1, its pharmaceutically acceptable salt, stereoisomer, or deuterated derivative, wherein the compound is selected from the following compounds, their pharmaceutically acceptable salts, stereoisomers, or deuterated derivatives: 、 、 、 、 、 、 、 。 7. The compound of claim 1, its pharmaceutically acceptable salt or deuterated derivative, wherein the compound is selected from the following compounds, their pharmaceutically acceptable salts or deuterated derivatives: 、 、 、 。 8. A pharmaceutical composition comprising the compound of any one of claims 1-7, a pharmaceutically acceptable salt, stereoisomer or deuterated thereof, and a pharmaceutically acceptable carrier.

9. The compound of any one of claims 1-7, its pharmaceutically acceptable salt, stereoisomer or deuterated derivative, or the pharmaceutical composition of claim 8, in the preparation of a treatment for 5-HT 2A Application in drugs for receptor-related diseases.

10. The application according to claim 9, wherein the 5-HT 2A Receptor-related diseases include: Schizophrenia, psychosis, schizoaffective disorder, mania, psychotic depression, affective disorder, dementia, anxiety disorder, sleep disorder, appetite disorder, bipolar disorder, psychosis secondary to hypertension, migraine, hypertension, thrombosis, vasospasm, ischemia, motor tic disorder, depression, major depressive disorder, anxiety, sleep disturbances and appetite disorders, nonmotor symptoms of Parkinson's disease (including delusions, hallucinations, depression, anxiety, cognitive impairment or sleep disturbances), dementia-related mental illnesses, negative symptoms of schizophrenia, Parkinson's disease, Huntington's disease, Alzheimer's disease, spinocerebellar atrophy, Tourette syndrome, Friedreich ataxia, Machado-Joseph disease, Lewy body dementia, movement disorders, dystonia, myoclonus, tremor or progressive supranuclear palsy and frontotemporal dementia.

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